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Abstract:

Compounds of the general formula (I) wherein each of m and n is
independently 0 or 1; R1 and R2, together with the carbon atom
to which they are attached, form a heterocyclic ring comprising one or
two heteroatoms selected from oxygen, sulfur, --S(O)-- and --S(0)2-;
R3 is --CHF2, --CF3, --OCHF2, --OCF3,
--SCHF2 or --SCF3; X is a bond, --CH2--, or --NH--; A is
aryl, cycloalkyl, cycloalkenyl, arylalkyl, heteroaryl, heteroarylalkyl,
heterocycloalkyl or heterocycloalkenyl, optionally substituted with one
or more, same or different substituents selected from R4; and
R4 is hydrogen, amino, thioxo, alkyl, haloalkyl, hydroxyalkyl,
alkoxy, haloalkoxy, halogen, oxo, thia, or hydroxy; or pharmaceutically
acceptable salts, hydrates or solvates thereof, have been found to
exhibit PDE4 inhibiting activity, and may therefore be useful in the
treatment of inflammatory diseases and disorders.
##STR00001##

Claims:

1. A compound of general formula I ##STR00023## wherein each of m and n
is independently 0 or 1; R1 and R2, together with the carbon
atom to which they are attached, form a heterocyclic ring comprising one
or two heteroatoms selected from oxygen, sulfur, --S(O)-- and
--S(O)2--; R3 is --CHF2, --CF3, --OCHF2,
--OCF3, --SCHF2 or --SCF3; X is a bond, --CH2--, or
--NH--; A is aryl, cycloalkyl, cycloalkenyl, arylalkyl, heteroaryl,
heteroarylalkyl, heterocycloalkyl or heterocycloalkenyl, optionally
substituted with one or more, same or different substituents selected
from R4; and R4 is hydrogen, amino, thioxo, alkyl, haloalkyl,
hydroxyalkyl, alkoxy, haloalkoxy, halogen, oxo, thia, or hydroxy; or a
pharmaceutically acceptable salt, hydrate or solvate thereof.

2. A compound according to claim 1 wherein X is --CH2-- or --NH--;

3. A compound according to claim 1 or 2 of general formula IIa
##STR00024## wherein m, n, R1, R2 and R3 are as defined
in claim 1.

4. A compound according to claim 1, wherein m and n are both 0.

5. A compound according to claim 1, wherein m and n are both 1.

6. A compound according to claim 1, wherein R3 is --OCHF2 or
--OCF.sub.3.

7. A compound according to claim 6, wherein R3 is --OCHF.sub.2.

8. A compound according to claim 1, wherein R3 is --SCHF2 or
--SCF.sub.3.

9. A compound according to claim 1, wherein R1 and R2, together
with the carbon atom to which they are attached, form a 4-, 5- or
6-membered heterocyclic ring.

15. A compound according to claim 1 for use in the treatment of
inflammatory diseases such as bronchial asthma, COPD, allergic rhinitis,
and nephritis; autoimmune diseases such as rheumatoid arthritis, multiple
sclerosis, Crohn's disease, and systemic lupus erythematosus; diseases of
the central nervous system such as depression, amnesia, and dementia;
organopathy associated with ischemic reflux caused by cardiac failure,
shock, and cerebrovascular diseases, and the like; insulin-resistant
diabetes; wounds; cancer; proliferative and inflammatory skin disorders
such as psoriasis, epidermal inflammation, acne, dermatitis, atopic
dermatitis, seborrheic dermatitis, contact dermatitis, urticaria,
pruritis and eczema; and other skin conditions such as alopecia, skin
atrophy, steroid induced skin atrophy, skin ageing and photo skin ageing.

16. A pharmaceutical composition comprising, as a therapeutically active
ingredient, a compound according to claim 1 and a pharmaceutically
acceptable carrier or vehicle.

17. A composition according to claim 16, wherein the pharmaceutically
acceptable carrier or vehicle is one that is suitable for oral
administration.

18. A composition according to claim 16 or 17 further comprising one or
more additional therapeutically active ingredients.

19. A method of preventing, treating or ameliorating an inflammatory
disease or condition, the method comprising administering to a patient in
need thereof a therapeutically effective amount of a compound according
to claim 1.

20. The method of claim 19, wherein the disease or condition is selected
from the group consisting of inflammatory diseases such as bronchial
asthma, COPD, allergic rhinitis, and nephritis; autoimmune diseases such
as rheumatoid arthritis, multiple sclerosis, Crohn's disease, and
systemic lupus erythematosus; diseases of the central nervous system such
as depression, amnesia, and dementia; organopathy associated with
ischemic reflux caused by cardiac failure, shock, and cerebrovascular
diseases, and the like; insulin-resistant diabetes; wounds; cancer;
proliferative and inflammatory skin disorders such as psoriasis,
epidermal inflammation, acne, dermatitis, atopic dermatitis, seborrheic
dermatitis, contact dermatitis, urticaria, pruritis and eczema; and other
skin conditions such as alopecia, skin atrophy, steroid induced skin
atrophy, skin ageing and photo skin ageing.

21. The method of claim 19 or 20, wherein the compound is administered by
the oral route.

Description:

FIELD OF INVENTION

[0001] The present invention relates to novel compounds with
phosphodiesterase inhibitory activity, as well as to their use as
therapeutic agents in the treatment of inflammatory diseases and
conditions.

BACKGROUND OF THE INVENTION

[0002] Phosphodiesterases are enzymes that catalyse the hydrolysis of
cyclic AMP and/or cyclic GMP in cells to 5-AMP and 5-GMP, respectively,
and as such they are critical to cellular regulation of cAMP or cGMP
levels. Of the 11 phosphodiesterases identified so far, phosphodiesterase
(PDE) 4, PDE7 and PDE8 are selective for cAMP. PDE4 is the most important
modulator of cAMP expressed in immune and inflammatory cells such as
neutrophils, macrophages and T-lymphocytes (Z. Huang and J. A. Mancini,
Current Med. Chem. 13, 2006, pp. 3253-3262). As cAMP is a key second
messenger in the modulation of inflammatory responses, PDE4 has been
found to regulate inflammatory responses of inflammatory cells by
modulating proinflammatory cytokines such as TNFα, IL-2,
IFN-γ, GM-CSF and LTB4. Inhibition of PDE4 has therefore become an
attractive target for the therapy of inflammatory diseases such as
asthma, chronic obstructive pulmonary disease (COPD), rheumatoid
arthritis, atopic dermatitis, Crohn's disease etc. (M. D. Houslay et al.,
Drug Discovery Today 10 (22), 2005, pp. 1503-1519). As atopic dermatitis
(AD) patients have increased PDE-activity, PDE4-inhibition would also
appear to be a viable treatment of AD (Journal of Investigative
Dermatology (1986), 87(3), 372-6).

[0003] The PDE4 gene family consists at least of four genes, A, B, C and
D, which have a high degree of homology (V. Boswell Smith and D. Spina,
Curr. Opinion Investig. Drugs 6(11), 2006, pp. 1136-1141). The four PDE4
isoforms are differentially expressed in different tissues and cell
types. Thus, PDE4B is predominantly expressed in monocytes and
neutrophils, but not in cortex and epithelial cells, while PDE4D is
expressed in lung, cortex, cerebellum and T-cells (C. Kroegel and M.
Foerster, Exp. Opinion Investig. Drugs 16(1), 2007, pp. 109-124). It has
been speculated that inhibition of PDE4D in the brain is associated with
the adverse effects found when administering PDE4 inhibitors clinically,
primarily nausea and emesis, whereas inhibition of PDE4B is associated
with anti-inflammatory effects (B. Lipworth, Lancet 365, 2005, pp.
167-175). However, the PDE inhibitors developed so far are not believed
to be specific for any of the four PDE4 isoforms.

[0004] Numerous PDE4 inhibitors have been studied for their therapeutic
effect on inflammatory diseases, primarily asthma, inflammatory bowel
disease and COPD. The first of these, theophylline, is a weak,
non-selective phosphodiesterase inhibitor used in the treatment of
respiratory diseases such as asthma and COPD. Treatment with theophylline
may, however, give rise to both mild and severe adverse effects, e.g.
arrhythmia and convulsions, restricting the clinical utility of
theophylline (Kroegel and Foerster, supra). As phosphodiesterase has
remained an attractive target for anti-inflammatory therapy, several
other, more selective PDE4 inhibitors have been developed and
investigated in a clinical setting. The clinical development of many of
the first-generation PDE4 inhibitors such as rolipram was discontinued
due to dose-limiting side effects, primarily nausea and emesis.
Second-generation PDE4 inhibitors with apparently less pronounced adverse
effects are currently in clinical trials (Houslay, supra).

[0005] Recently developed PDE-4 inhibitors are for example disclosed in EP
0771794 and EP 0943613. WO 96/31476 discloses structurally different
4-substituted-3,5-dichloropyridines which are inhibitors of cyclic AMP
phosphodiesterase.

[0006] WO 2008/104175 discloses 4-substituted 3,5-dichloropyridine
compounds wherein the substituent comprises a spiro benzodioxole or
benzodioxepine heterocyclic ring system. These compounds are disclosed to
be PDE4 inhibitors, and are intended for topical administration as they
are subjected to degradation when administered orally.

[0007] An overview of preclinical and clinical trials with selective PDE4
inhibitors, including such inhibitors aimed for the treatment of atopic
dermatitis and psoriasis, was recently given in Inflammation & Allergy:
Drug Targets, 2007, 6(1), 17-26.

[0008] There is a continued need for developing novel PDE4 inhibitors
which have a more favourable therapeutic window, i.e. fewer adverse
effects upon oral administration, while retaining their therapeutic
anti-inflammatory effect.

SUMMARY OF THE INVENTION

[0009] The inventors have surprisingly found that the compounds of the
present invention exhibit PDE4 inhibitory activity upon oral
administration and may be useful as therapeutic agents for systemic
treatment of inflammatory allergic diseases such as bronchial asthma,
COPD, allergic rhinitis, and nephritis; autoimmune diseases such as
rheumatoid arthritis, multiple sclerosis, Crohn's disease, and systemic
lupus erythematosus; diseases of the central nervous system such as
depression, amnesia, and dementia; organopathy associated with ischemic
reflux caused by cardiac failure, shock, and cerebrovascular diseases,
and the like; insulin-resistant diabetes; wounds; and other diseases
where inflammation plays a part in the etiology or progression of the
disease.

[0011] Accordingly, the present invention relates to a compound of general
formula I

##STR00002##

wherein each of m and n is independently 0 or 1; R1 and R2,
together with the carbon atom to which they are attached, form a
heterocyclic ring comprising one or two heteroatoms selected from oxygen,
sulfur, --S(O)-- and --S(O)2--;

R3 is --CHF2, --CF3, --OCHF2, --OCF3,
--SCHF2 or --SCF3;

[0012] X is a bond, --CH2--, or --NH--; A is aryl, cycloalkyl,
cycloalkenyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or
heterocycloalkenyl, optionally substituted with one or more, same or
different substituents selected from R4; and R4 is hydrogen,
amino, thioxo, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy,
halogen, oxo, thia, or hydroxy; or a pharmaceutically acceptable salt,
hydrate, or solvate thereof.

[0013] Compounds of a similar chemical structure are known from WO
2008/104175. These compounds are generally known to be quickly
metabolised and inactivated upon systemic/oral administration as the
methoxy group (R3═OCH3) is cleaved to a hydroxyl group
(R3═OH) as shown in example 15. However, in the compounds of
this invention, metabolism of R3 and hence inactivation is
substantially reduced. Thus, for instance when A is 3,5-dichloropyridine
the compounds of formula IIa are metabolised to the metabolically more
stable and active N-oxide (IIb) and when A is
3,5-dichloropyridine-N-oxide the compounds are generally metabolically
stable making the compounds suited for systemic, in particular oral,
administration--cf. example 15.

[0014] In another aspect, the invention relates to compounds of general
formula I for use in therapy.

DETAILED DISCLOSURE OF THE INVENTION

Definitions

[0015] The term "hydrocarbon radical" is intended to indicate a radical
containing only hydrogen and carbon atoms, it may contain one or more
double and/or triple carbon-carbon bonds, and it may comprise cyclic
moieties in combination with branched or linear moieties. Said
hydrocarbon comprises 1-20 carbon atoms, and preferably comprises 1-12,
e.g. 1-6, e.g. 1-4, e.g. 1-3, e.g. 1-2 carbon atoms. The term includes
alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkynyl and aryl, arylalkyl.

[0016] The term "aryl" is intended to indicate a radical of aromatic
carbocyclic rings comprising 6-20 carbon atoms, such as 6-14 carbon
atoms, preferably 6-10 carbon atoms, in particular 5- or 6-membered
rings, optionally fused carbocyclic rings with at least one aromatic
ring, such as phenyl, naphthyl, indenyl and indanyl.

[0018] In the present context, the term "alkyl" is intended to indicate
the radical obtained when one hydrogen atom is removed from a
hydrocarbon. Said alkyl comprises 1-20, preferably 1-12, such as 1-6,
such as 1-4 carbon atoms. The term includes the subclasses normal alkyl
(n-alkyl), secondary and tertiary alkyl, such as methyl, ethyl, n-propyl,
isopropyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl, isopentyl,
hexyl and isohexyl.

[0020] The term "heterocycloalkyl" is intended to indicate a cycloalkane
radical as described above, wherein one or more carbon atoms are replaced
by heteroatoms, comprising 1-19 carbon atoms, e.g. 2-4 carbon atoms,
further comprising 1-6 heteroatoms, preferably 1, 2, or 3 heteroatoms,
selected from O, N, or S, which may optionally be oxidised once or twice,
e.g. [1,3]dioxole, oxetane, [1,3]dioxolane, [1,3]dioxane,
tetrahydrothiopyran, tetrahydrothiopyran-1,1-dioxide,
tetrahydrothiopyran-1-oxide, piperidine, tetrahydrothiophene,
[1,3]-dithiane, thietane, [1,3]-dithiane-1,3-dioxide, or
thietane-1-oxide, or including fused bicyclic rings with 1-4 heteroatoms,
wherein at least one ring comprises a heteroatom, and wherein the other
ring may for example be a carbocyclic ring, e.g. isoindolyl.

[0022] The term "heterocycloalkenyl" is intended to indicate a cycloalkene
radical as described above, wherein one or more carbon atoms are replaced
by heteroatoms, comprising 1-19 carbon atoms, e.g. 2-4 carbon atoms,
further comprising 1-6 heteroatoms, preferably 1, 2, or 3 heteroatoms,
selected from O, N, or S, including fused bicyclic rings with 1-4
heteroatoms, wherein at least one ring comprises a heteroatom and wherein
the other ring may for example be a carbocyclic ring, e.g.
dihydrofuranyl, or 2,5-dihydro-1H-pyrrolyl.

[0023] The term "arylalkyl" is intended to indicate an aryl radical as
defined above covalently joined to an alkyl group, e.g. benzyl.

[0024] The term "heteroarylalkyl" is intended to indicate a heteroaryl
radical as defined above covalently joined to an alkyl group.

[0025] The term "halogen" is intended to indicate a substituent from the
7th main group of the periodic table, such as fluoro, chloro, bromo
and iodo.

[0026] The term "haloalkyl" is intended to indicate an alkyl group as
defined above substituted with one or more halogen atoms as defined
above, e.g. difluoromethyl.

[0027] The term "hydroxyalkyl" is intended to indicate an alkyl group as
defined above substituted with one or more hydroxy, e.g. hydroxymethyl,
hydroxyethyl, hydroxypropyl.

[0028] The term "alkoxy" is intended to indicate a radical of the formula
--OR', wherein R' is alkyl as indicated above, e.g. methoxy, ethoxy,
n-propoxy, isopropoxy, butoxy, etc.

[0029] The term "alkoxycarbonyl" is intended to indicate a radical of the
formula --C(O)--O--R', wherein R' is alkyl as indicated above, e.g.
methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl,
etc.

[0030] The term "alkylcarbonyl" is intended to indicate a radical of the
formula --C(O)--R', wherein R' is alkyl as indicated above, e.g.
ethanoyl, acetyl.

[0031] The term "heterocyclic ring" is intended to indicate a heteroaryl,
heterocycloalkyl and heterocycloalkenyl, wherein one or more carbon atoms
are replaced by heteroatoms, comprising 1-19 carbon atoms, e.g. 2-4
carbon atoms, further comprising 1-6 heteroatoms, preferably 1, 2, or 3
heteroatoms, selected from O, N, or S, which may optionally be oxidised
once or twice, e.g. [1,3]dioxole, oxetane, [1,3]dioxolane, [1,3]dioxane,
tetrahydrothiopyran, tetrahydrothiopyran-1,1-dioxide,
tetrahydrothiopyran-1-oxide, piperidine, tetrahydrothiophene,
[1,3]-dithiane, thietane, [1,3]-dithiane-1,3-dioxide, or
thietane-1-oxide, or including fused bicyclic rings with 1-4 heteroatoms,
wherein at least one ring comprises a heteroatom, and wherein the other
ring may for example be a carbocyclic ring, e.g. isoindolyl.

[0033] The term "solvate" is intended to indicate a species formed by
interaction between a compound, e.g. a compound of formula I, and a
solvent, e.g. alcohol, glycerol or water, wherein said species are in a
solid form. When water is the solvent, said species is referred to as a
hydrate.

Embodiments of the Invention

[0034] In currently favoured embodiments, the invention relates to
compounds of general formula I wherein X is --CH2-- or --NH--.

[0035] In another embodiment, the invention relates to compounds of
general formula IIa

##STR00003##

wherein m, n, R1, R2 and R3 are as described above.

[0036] In one embodiment, m and n in formula IIa and IIb are both 0. In
another embodiment, m and n in formula IIa and IIb are both 1.

[0037] In an embodiment, R3 is --OCHF2 or --OCF3, such as
--OCHF2.

[0038] In another embodiment, R3 is --SCHF2 or --SCF3.

[0039] In an embodiment, R1 and R2, together with the carbon
atom to which they are attached, form a 4-, 5- or 6-membered heterocyclic
ring. The heterocyclic ring may comprise one heteroatom, e.g. selected
from oxygen or --S(O)2. Specific examples of heterocyclic rings are
tetrahydropyran, oxetane, [1,3]dioxolane, [1,3]dioxane,
tetrahydrothiopyran, tetrahydrothiopyran-1,1-dioxide,
tetrahydrothiopyran-1-oxide, tetrahydrothiophene, [1,3]-dithiane,
thietane, [1,3]-dithiane-1,3-dioxide, thietane-1-oxide, or
thiethane-1,1-dioxide.

[0052] The compounds of the present invention may typically have a
molecular weight below 800 Dalton, such as below 750 Dalton, e.g. below
700 Dalton, or below 650, 600, 550, or 500 Dalton.

[0053] The compounds of the invention may be obtained in crystalline form
either directly by concentration from an organic solvent or by
crystallisation or recrystallisation from an organic solvent or mixture
of said solvent and a cosolvent that may be organic or inorganic, such as
water. The crystals may be isolated in essentially solvent-free form or
as a solvate, such as a hydrate. The invention covers all crystalline
modifications and forms and also mixtures thereof.

[0054] Compounds of the invention may or may not comprise asymmetrically
substituted (chiral) carbon atoms which give rise to the existence of
isomeric forms, e.g. enantiomers and possibly diastereomers. The present
invention relates to all such isomers, either in pure form or as mixtures
thereof (e.g. racemates). Pure stereoisomeric forms of the compounds and
the intermediates of this invention may be obtained by the application of
procedures known in the art. The various isomeric forms may be separated
by physical separation methods such as selective crystallization and
chromatographic techniques, e.g. liquid chromatography using chiral
stationary phases.

[0055] Enantiomers may be separated from each other by the selective
crystallization of their diastereomeric salts with optically active
amines, such as I-ephedrine. Alternatively, enantiomers may be separated
by chromatographic techniques using chiral stationary phases. Said pure
stereoisomeric forms may also be derived from the corresponding pure
stereoisomeric forms of the appropriate starting materials, provided that
the reaction occurs stereoselectively or stereospecifically. Preferably,
if a specific stereoisomer is desired, said compound will be synthesized
by stereoselective or stereospecific methods of preparation. These
methods will advantageously employ chiral pure starting materials.

[0057] Besides being useful for human treatment, the compounds of the
present invention may also be useful for veterinary treatment of animals
including mammals such as horses, cattle, sheep, pigs, dogs, and cats.

[0058] For use in therapy, compounds of the present invention are
typically in the form of a pharmaceutical composition. The invention
therefore relates to a pharmaceutical composition comprising a compound
of formula Ia or Ib, optionally together with one or more other
therapeutically active compound(s), together with a pharmaceutically
acceptable excipient or vehicle. The excipient must be "acceptable" in
the sense of being compatible with the other ingredients of the
composition and not deleterious to the recipient thereof.

[0059] Conveniently, the active ingredient comprises from 0.05-99.9% by
weight of the formulation.

[0060] In the form of a dosage unit, the compound may be administered one
or more times a day at appropriate intervals, always depending, however,
on the condition of the patient, and in accordance with the prescription
made by the medical practitioner. Conveniently, a dosage unit of a
formulation contain between 0.1 mg and 1000 mg, preferably between 1 mg
and 100 mg, such as 5-50 mg of a compound of formula I.

[0061] A suitable dosage of the compound of the invention will depend,
inter alia, on the age and condition of the patient, the severity of the
disease to be treated and other factors well known to the practising
physician. The compound may be administered either orally, parenterally
or topically according to different dosing schedules, e.g. daily or with
weekly intervals. In general a single dose will be in the range from 0.01
to 400 mg/kg body weight. The compound may be administered as a bolus
(i.e. the entire daily dosis is administered at once) or in divided doses
two or more times a day.

[0062] In the context of topical treatment it may be more appropriate to
refer to a "usage unit", which denotes a single dose which is capable of
being administered to a patient, and which may be readily handled and
packed, remaining as a physically and chemically stable unit dose
comprising either the active material as such or a mixture of it with
solid or liquid pharmaceutical diluents or carriers.

[0063] The term "usage unit" in connection with topical use means a
unitary, i.e. a single dose capable of being administered topically to a
patient in an application per square centimetre of the infected area of
from 0.1 mg to 10 mg, and preferably from 0.2 mg to 1 mg, of the active
ingredient in question.

[0064] It is also envisaged that in certain treatment regimes,
administration with longer intervals, e.g. every other day, every week,
or even with longer intervals may be beneficial.

[0065] If the treatment involves administration of another therapeutically
active compound it is recommended to consult Goodman & Gilman's The
Pharmacological Basis of Therapeutics, 9th Ed., J. G. Hardman and L. E.
Limbird (Eds.), McGraw-Hill 1995, for useful dosages of said compounds.

[0066] The administration of a compound of the present invention with one
or more other active compounds may be either concomitantly or
sequentially.

[0067] The formulations include e.g. those in a form suitable for oral
(including sustained or timed release), rectal, parenteral (including
subcutaneous, intraperitoneal, intramuscular, intraarticular and
intravenous), transdermal, ophthalmic, topical, dermal, nasal or buccal
administration. Topical administration of the claimed formulation is
particularly suitable.

[0068] The formulations may conveniently be presented in dosage unit form
and may be pre-pared by any of the methods well known in the art of
pharmacy, e.g. as disclosed in Remington, The Science and Practice of
Pharmacy, 20th ed., 2000. All methods include the step of bringing
the active ingredient into association with the carrier, which
constitutes one or more accessory ingredients. In general, the
formulations are prepared by uniformly and intimately bringing the active
ingredient into association with a liquid carrier or a finely divided
solid carrier or both, and then, if necessary, shaping the product into
the desired formulation.

[0069] Formulations of the present invention suitable for oral
administration may be in the form of discrete units as capsules, sachets,
tablets or lozenges, each containing a predetermined amount of the active
ingredient; in the form of a powder or granules; in the form of a
solution or a suspension in an aqueous liquid or non-aqueous liquid, such
as ethanol or glycerol; or in the form of an oil-in-water emulsion or a
water-in-oil emulsion. Such oils may be edible oils, such as e.g.
cottonseed oil, sesame oil, coconut oil or peanut oil. Suitable
dispersing or suspending agents for aqueous suspensions include synthetic
or natural gums such as tragacanth, alginate, acacia, dextran, sodium
carboxymethylcellulose, gelatin, methylcellulose,
hydroxypropylmethylcellulose, hydroxypropylcellulose, carbomers and
polyvinylpyrrolidone. The active ingredients may also be administered in
the form of a bolus, electuary or paste.

[0070] A tablet may be made by compressing or moulding the active
ingredient optionally with one or more accessory ingredients. Compressed
tablets may be prepared by compressing, in a suitable machine, the active
ingredient(s) in a free-flowing form such as a powder or granules,
optionally mixed by a binder, such as e.g. lactose, glucose, starch,
gelatine, acacia gum, tragacanth gum, sodium alginate,
carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,
polyethylene glycol, waxes or the like; a lubricant such as e.g. sodium
oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium
acetate, sodium chloride or the like; a disintegrating agent such as e.g.
starch, methylcellulose, agar, bentonite, croscarmellose sodium, sodium
starch glycollate, crospovidone or the like or a dispersing agent, such
as polysorbate 80. Moulded tablets may be made by moulding, in a suitable
machine, a mixture of the powdered active ingredient and suitable carrier
moistened with an inert liquid diluent.

[0071] Formulations for rectal administration may be in the form of
suppositories in which the compound of the present invention is admixed
with low melting water soluble or insoluble solids such as cocoa butter,
hydrogenated vegetable oils, polyethylene glycol or fatty acids esters of
polyethylene glycols, while elixirs may be prepared using myristyl
palmitate.

[0072] Formulations suitable for parenteral administration conveniently
comprise a sterile oily or aqueous preparation of the active ingredients,
which is preferably isotonic with the blood of the recipient, e.g.
isotonic saline, isotonic glucose solution or buffer solution. The
formulation may be conveniently sterilised by for instance filtration
through a bacteria retaining filter, addition of sterilising agent to the
formulation, irradiation of the formulation or heating of the
formulation. Liposomal formulations as disclosed in e.g. Encyclopedia of
Pharmaceutical Technology, vol. 9, 1994, are also suitable for parenteral
administration.

[0073] Alternatively, the compounds of formula I may be presented as a
sterile, solid preparation, e.g. a freeze-dried powder, which is readily
dissolved in a sterile solvent immediately prior to use.

[0074] Transdermal formulations may be in the form of a plaster or a
patch.

[0075] Formulations suitable for ophthalmic administration may be in the
form of a sterile aqueous preparation of the active ingredients, which
may be in microcrystalline form, for example, in the form of an aqueous
microcrystalline suspension. Liposomal formulations or biodegradable
polymer systems e.g. as disclosed in Encyclopedia of Pharmaceutical
Technology, vol. 2, 1989, may also be used to present the active
ingredient for ophthalmic administration.

[0076] Formulations suitable for topical or ophthalmic administration
include liquid or semi-liquid preparations such as liniments, lotions,
gels, sprays, foams, oil-in-water or water-in-oil emulsions such as
creams, ointments or pastes; or solutions or suspensions such as drops.
Compositions for ophthalmic treatment may preferably additionally contain
a cyclodextrin.

[0077] For topical administration, the compound of formula I may typically
be present in an amount of from 0.01 to 20% by weight of the composition,
such as 0.1% to about 10%, but may also be present in an amount of up to
about 50% of the composition.

[0079] In addition to the aforementioned ingredients, the formulations of
a compound of formula I may include one or more additional ingredients
such as diluents, buffers, flavouring agents, colourant, surface active
agents, thickeners, preservatives, e.g. methyl hydroxybenzoate (including
anti-oxidants), emulsifying agents and the like.

[0080] When the active ingredient is administered in the form of salts
with pharmaceutically acceptable non-toxic acids or bases, preferred
salts are for instance easily water-soluble or slightly soluble in water,
in order to obtain a particular and appropriate rate of absorption.

[0082] The invention is described in further detail in the following
examples which are not in any way intended to limit the scope of the
invention as claimed.

Methods of Preparation

[0083] The compounds of the present invention can be prepared in a number
of ways well known to those skilled in the art of synthesis. The
compounds of formula I may for example be prepared using the reactions
and techniques outlined below together with methods known in the art of
synthetic organic chemistry, or variations thereof as appreciated by
those skilled in the art. Preferred methods include, but are not limited
to, those described below. The reactions are carried out in solvents
appropriate to the reagents and materials employed and suitable for the
transformations being effected. Also, in the synthetic methods described
below, it is to be understood that all proposed reaction conditions,
including choice of solvent, reaction atmosphere, reaction temperature,
duration of experiment and work-up procedures, are chosen to be
conditions of standard for that reaction, which should be readily
recognized by one skilled in the art. Not all compounds falling into a
given class may be compatible with some of the reaction conditions
required in some of the methods described. Such restrictions to the
substituents which are compatible with the reaction conditions will be
readily apparent to one skilled in the art and alternative methods can be
used.

[0084] Starting materials are either known compounds which are
commercially available, or they may be prepared by routine synthetic
methods well known to a person skilled in the art.

[0085] The compounds of the present invention or any intermediate may be
purified if required using standard methods well known to a synthetic
organist chemist, e.g. methods described in "Purification of Laboratory
Chemicals", 5th ed. 2003. Starting materials are either known
compounds, commercially available, or they may be prepared by routine
synthetic methods well known to a person skilled in the art.

General Procedures, Preparations and Examples

[0086]1H nuclear magnetic resonance (NMR) spectra were recorded at
300 MHz and 13C NMR spectra at 75.6 MHz. Chemical shift values
(δ, in ppm) are quoted in the specified solvent relative to
internal tetramethylsilane (δ=0.00) or chloroform (δ=7.25) or
deuteriochloroform (δ=76.81 for 13C NMR) standards. The value
of a multiplet, either defined (doublet (d), triplet (t), quartet (q)) or
not (m) at the approximate mid point is given unless a range is quoted.
(bs) indicates a broad singlet. The organic solvents used were usually
anhydrous. Chromatography was performed on Merck silica gel 60
(0.040-0-063 mm). The solvent ratios indicated refer to v:v unless
otherwise noted.

[0092] The compounds of the invention can for example be prepared as
follows. Compounds of the general formula IIa and IIb, wherein n, m,
R1, R2 are as defined above and R3═OCF2H can be
prepared as follows:

##STR00004##

[0093] Starting materials of formula 3a are prepared according to standard
procedures known to a person skilled in the art (WO 2008/104175).
Selective de-alkylation of 3a using a sulphur nucleophile e.g. t-dodecyl
mercaptane affords 4a.

[0094] Reaction of compounds with formula 4a with sodium
chlorodifluoroacetate in the presence of a base e.g. K2CO3 in a
suitable solvent such as DMF at temperatures from room temperature to
140° C. give compounds of the formula IIa.

[0095] Oxidation of IIa with 3-chloroperbenzoic acid or
H2O2/methyltrioxorhenium(VII) in a suitable solvent such as DCM
afforded compounds of the general formula IIb Compounds of the general
formula I wherein X═--NH-- can for example be prepared as described
in WO 2008/104175, which is hereby incorporated by reference, and as
described in example 10 and example 11 in the present application.

[0097] A solution of
2-(3,5-Dichloropyridin-4-yl)-1-{9-methoxy-spiro[2H-1,5-benzodioxepin-3(4H-
), 3'-oxetane]-6-yl}ethanone (272 mg, 0.7 mmol) in anhydrous DMF (4 mL)
was added K2CO3 (916 mg, 7 mmol) and t-dodecyl mercaptan (3.12 ml, 13
mmol). The mixture was heated, with stirring, at 140° C. in a
sealed tube for 16 h. The mixture was allowed to cool to r.t. and water
(20 ml) was added. After neutralisation with 4N HCl the mixture was
extracted with DCM. The combined organic phase was washed with brine,
dried over MgSO4 and evaporated to dryness under reduced pressure.
Chromatography yielded the product 401.

[0100] A solution of
2-(3,5-Dichloropyridin-4-yl)-1-{9-hydroxy-spiro[2H-1,5-benzodioxepin-3(4H-
), 3'-oxetane]-6-yl}ethanone [401](1.66 g, 4.2 mmol) in DMF (12 mL) and
water (1.3 ml) was added K2CO3 (1.45 g, 10.5 mmol) and sodium
chlorodifluoroacetate (1.28 g, 8.4 mmol). The mixture was heated under
Argon, with stirring, at 100° C. in a sealed tube for 1.5 h.
Additional 950 mg of sodium chlorodifluoroacetate was added and heating
was continued for 1 h. Additional 950 mg of sodium chlorodifluoroacetate
and 1.45 g K2CO3 was added, heating continued for 5 h. Another portion of
950 mg of sodium chlorodifluoroacetate and 1.45 g K2CO3 was added,
heating continued for 2 h. The mixture was allowed to cool to rt, added
water (200 ml) and pH was adjusted to 3 using 4N HCl. The mixture was
extracted with DCM and the combined organic phase was washed with brine,
dried over MgSO4 and evaporated to dryness under reduced pressure.
Chromatography yielded 793 mg of the product 101.

[0103] A solution of
2-(3,5-Dichloropyridin-4-yl)-1-{9-difluoromethoxy-spiro[2H-1,5-benzodioxe-
pin-3(4H), 3'-oxetane]-6-yl}ethanone [101](792 mg, 1.8 mmol) in DCM (15
ml) was added 3-chloroperbenzoic acid (1.2 g, 7 mmol) and the mixture was
stirred at rt for 4 h. Additional 3-chloroperbenzoic acid (0.6 g, 3.5
mmol) was added and stirring was continued for 16 h. The reaction mixture
was washed with Na2CO3 and subsequently brine, dried over MgSO4 and
evaporated to dryness under reduced pressure. Chromatography yielded an
almost pure product which subsequently was suspended in EtOAc and
filtered off yielding 464 mg of 102

[0106] A solution of
2-(3,5-Dichloropyridin-4-yl)-1-{9-methoxy-spiro[2H-1,5-benzodioxepin-3(4H-
), 4'-tetrahydropyran]-6-yl}ethanone (351 mg, 0.8 mmol) in anhydrous DMF
(6 mL) was added K2CO3 (1.1 g, 8 mmol) and t-dodecyl mercaptan (3.8 ml,
16 mmol). The mixture was heated, with stirring, at 140° C. in a
sealed tube for 22 h. The mixture was allowed to cool to r.t. and water
was added. After neutralisation with 4N HCl the mixture was extracted
with DCM (2×50 ml). The combined organic phase was extracted twice
with 2N NaOH. The aqueous phase was washed twice with DCM, neutralised
with 4N HCL and finally extracted with DCM. The organic phase was washed
with brine, dried over MgSO4 and evaporated to dryness under reduced
pressure. Chromatography yielded the product 402 as a yellow powder (118
mg)

[0109] A solution of
2-(3,5-Dichloropyridin-4-yl)-1-{9-hydroxy-spiro[2H-1,5-benzodioxepin-3(4H-
), 4'-tetrahydropyran]-6-yl}ethanone [402](118 mg, 0.28 mmol) in anhydrous
DMF (6 mL) was added K2CO3 (76 mg, 0.55 mmol) and sodium
chlorodifluoroacetate (84 mg, 0.55 mmol). The mixture was heated under
Argon, with stirring, at 100° C. in a sealed tube for 1.5 h.
Additional K2CO3 (76 mg, 0.55 mmol) and sodium chlorodifluoroacetate (84
mg, 0.55 mmol) was added and stirring was continued at 80° C. for
6 h. The mixture was allowed to cool to rt, added water and the mixture
was neutralised using 4N HCl. The mixture was extracted with DCM and the
combined organic phase was washed with brine, dried over MgSO4 and
evaporated to dryness under reduced pressure. Chromatography yielded 40
mg of the product 103.

[0115] A solution of
2-(3,5-Dichloropyridine-4-yl)-1-(7-methoxy-2',3',5',6'-tetrahydro-spiro[1-
,3-benzodioxole-2,4'-(4H)-pyran]-4-yl)ethanone (325 mg, 0.8 mmol) in
anhydrous DMF (5 ml) was added K2CO3 (1.1 g, 8 mmol) and t-dodecyl
mercaptan (3.7 ml, 16 mmol). The mixture was heated, with stirring, at
140° C. in a sealed tube for 16 h. The mixture was allowed to cool
to r.t. and water was added. After neutralisation with 4N HCl the mixture
was extracted with DCM (2×50 ml). The combined organic phase was
extracted twice with 2N NaOH. The aqueous phase was washed twice with
DCM, neutralised with 4N HCL and finally extracted with DCM (3×75
ml). The organic phase was dried over MgSO4 and evaporated to dryness
under reduced pressure. Chromatography yielded the product 403 as a white
powder (192 mg)

[0124] A solution of
2-(3,5-Dichloropyridine-4-yl)-1-(7-methoxy-2',3',5',6'-tetrahydro-spiro[1-
,3-benzodioxole-2,4'-(4H)-thiopyran]-4-yl)ethanone (8.3 g, 19.5 mmol) in
anhydrous DMF (80 mL) was added K2CO3 (27 g, 195 mmol) and t-dodecyl
mercaptan (92 ml, 390 mmol). The mixture was heated, with stirring, at
140° C. in a sealed tube for 21 h. Additional K2CO3 (13 g) and
t-dodecyl mercaptan (45 ml) was added. Stirring was continued for
additional 5 h. The mixture was allowed to cool to r.t. and water was
added. After neutralisation with 4N HCl the mixture was extracted with
DCM (3×200 ml). The combined organic phase was washed with brine,
dried over MgSO4 and evaporated to dryness under reduced pressure. Flash
chromatography gave a crude product that was re-dissolved in DCM and
subsequently extracted twice with 2N NaOH. The aqueous phase was washed
twice with DCM, neutralised with 4N HCL and finally extracted with DCM
(3×150 ml). The organic phase was washed with brine, dried over
MgSO4 and evaporated to dryness under reduced pressure. Chromatography
yielded 2.56 g of the product 404.

[0127] A solution of
2-(3,5-Dichloropyridine-4-yl)-1-(7-hydroxy-2',3',5',6'-tetrahydro-spiro[1-
,3-benzodioxole-2,4'-(4H)-thiopyran]-4-yl)ethanone [404](4.27 g, 10.4
mmol) in anhydrous DMF (120 mL) was added K2CO3 (2.16 g, 15.6 mmol) and
sodium chlorodifluoroacetate (2.47 g, 15.6 mmol). The mixture was heated
under Argon, with stirring, at 100° C. for 40 min. The mixture was
allowed to cool to rt, added water (500 ml) and extracted with EtOAc
(2×400 ml). The combined organic phase was washed with water (500
ml) and saturated NaCl solution (150 ml) followed by drying over Na2SO4
and evaporated to dryness under reduced pressure. Chromatography yielded
2.64 g of the product 107 a yellow-white powder.

[0130] A solution of
2-(3,5-Dichloropyridine-4-yl)-1-(7-difluoromethoxy-2',3',5',6-tetrahydro--
spiro[1,3-benzodioxole-2,4''-(4H)-thiopyran]-4-yl)ethanone [107](2.64 g,
5.7 mmol) in chloroform (40 ml) was slowly added a solution of
3-chloroperbenzoic acid (5.76 g, 25.7 mmol) in chloroform (50
ml)--keeping the temperature between 21° C. and 24° C. The
mixture was stirred at rt for 19 h and added to a NaHCO3(aq) solution.
The organic phase was washed with an aqueous solution of NaCl. The
aqueous phases were extracted with DCM. The combined organic phases was
dried over Na2SO4 and evaporated to dryness under reduced pressure.
Chromatography yielded 1.95 g of the product 108 as a white powder.

[0133] A solution of
2-(3,5-Dichloropyridine-4-yl)-1-(7-methoxy-2',3',5',6'-tetrahydro-spiro[1-
,3-benzodioxole-2,4'-(4H)-thiopyran-1',1'-dioxide]-4-yl)ethanone (415 mg,
0.91 mmol) in anhydrous DMF (10 mL) was added K2CO3 (1.25 g, 9.1 mmol)
and t-dodecyl mercaptan (4.3 ml, 18 mmol). The mixture was heated, with
stirring, at 140° C. in a sealed tube for 16 h. The mixture was
allowed to cool to r.t. and water was added. After neutralisation with 4N
HCl the mixture was extracted with EtOAc (2×50 ml). The combined
organic phase was extracted twice with 2N NaOH. The aqueous phase was
washed twice with EtOAc, neutralised with 4N HCL and finally extracted
with EtOAc (2×100 ml). The organic phase was washed with brine,
dried over MgSO4 and evaporated to dryness under reduced pressure.
Chromatography yielded 204 mg of the product 405.

[0139] Methyl
7-Difluoromethoxy-2',3',5',6'-tetrahydro-spiro[1,3-benzodioxole-2,4'-(4H)-
-thiopyran]-4-carboxylate (437 mg) was dissolved in a mixture of Methanol
(5 mL) and THF (5 mL) and 1M aqueous Lithium hydroxide (3.9 mL) was
added. The ester was cleaved after 1 hour at 50° C. The solution
was cooled to room temperature and acidified with 2N sulfuric acid (1.95
mL) and the product was extracted into EtOAc.
7-Difluoromethoxy-2',3',5',6'-tetrahydro-spiro[1,3-benzodioxole-2,4'-(4H)-
-thiopyran]-4-carboxylic acid was obtained after removal of solvents under
reduced pressure.

[0141] 7-Difluoromethoxy-2',3',5',6'-tetrahydro-spiro[1,3-benzodioxole-2,4-
'-(4H)-thiopyran]-4-carboxylic acid (344 mg) was dissolved in dry DMF (3
mL). 4-Nitrophenol (226 mg) Ethyl-dimethylaminopropylcarbodiimide
hydrochloride (312 mg) and N,N-Dimethyl-4-aminopyridine (198 mg) was
added. After stirring at room temperature for 20 hours, aqueous work up
with tert-Butyl methyl ether and chromatography of the organics in a
gradient from 0 to 40% EtOAc in pentanes afforded the title compound as
an oil.

[0164] Human recombinant PDE4 (Genbank accession no NM--006203) was
incubated for 1 hour, with the test compound at concentrations up to 10
μM, with cAMP (1×10-5M), and with a low amount (0.021 MBq) of
radioactively labelled cAMP. At the end of the incubation, the cleavage
of the substrate was evaluated by the binding of the AMP product to SPA
beads, which generate chemoluminescence when bound to the radioactive
tracer. The AMP product inhibited the binding of the radioactive tracer
to the beads, and the luminescent signal was competed.

[0165] The results were calculated as the molar concentrations resulting
in 50% inhibition of the substrate cleavage compared to controls samples,
and are expressed as IC50 (M).

[0167] One rat is dosed orally (5 mg/kg--dissolved in
DMSO/H2O/propylenglycol [1:5:4]) and blood samples are taken from the
sublingual venous plexus at 30 min, 1 h, 2 h, 4 h and 6 h. Blood samples
are taken in BD Vacutainer SST serum separation tubes, serum is isolated
by centrifugation, transferred to micronics tubes and subsequently
analysed.

[0168] Mass spectrometer (API5000 series) parameters are optimised to
analyse for the specific compounds and test injections are performed to
confirm the validity of the established generic chromatography method.
The generic method is based on fast gradient (2.5 min) analysis on C18
column with mobile phases consisting methanol, ammonium acetate, formic
acid and water.

[0169] Standards are prepared in rat serum to cover the analytical range
0.1 to 300 ng/ml. Standards, blank serum and study samples are applied to
96 deepwell plate and proteins are precipitated by addition of
acetonitrile containing internal standard. Samples are analysed on
LC-MS/MS usually overnight. Integration and quantification is performed
on ration between analyte and internal standard using Analyst software
version 1.5. Pharmacokinetic parameters are calculated using a
standardised Excel spreadsheet.

[0170] In vivo pharmacokinetic profile in rat of compound 101 disclosed in
WO 2008/104175 and compound 105 and 106 disclosed in examples 5 and 6,
respectively: